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More than two years after a major New England Journal of Medicine study declared arthritis drug Celebrex safe for use in heart patients, new research published in JACC: Basic to Translational Science Feb. 22 suggests the drug might actually raise users’ risk for heart valve calcification.

Celebrex—a nonsteroidal anti-inflammatory drug (NSAID)—was found noninferior to predecessors like ibuprofen and naproxen in the NEJMstudy, published in late 2016, Meghan A. Bowler, PhD, and colleagues at Vanderbilt University wrote in JACC. But when Bowler and co-author David Merryman, PhD, tested the active compound in Celebrex (celecoxib) on valve cells in an effort to see if it could double as a treatment for aortic stenosis (AS), they were surprised to find celecoxib made the problem worse.

“Our investigation was motivated by the need for pharmaceutical alternatives to aortic valve replacement and the unique ability of celecoxib and dimethyl celecoxib to bind to cadherin-11 (CDH11), a recently identified target for calcific aortic valve disease (CAVD) and AS,” the authors wrote. “We have previously demonstrated that targeting CDH11 in vivo prevents the pathological increase in aortic jet maximum velocity, a clinical metric used to define the severity of AS.

“Others have found that celecoxib and its inactive analog, dimethyl celecoxib, were able to bind to CDH11, presenting an opportunity to exploit the off-target effects of celecoxib to treat CAVD with an already FDA-approved drug.”

In the four-year NEJM study, authors Steven E. Nissen, MD, et al. tested celecoxib against more traditional NSAIDs in a cohort of 24,081 patients who required the drugs either for osteoarthritis or rheumatoid arthritis. Though all patients were at an increased cardiovascular risk, those who took Celebrex saw better CV outcomes than patients taking naproxen and ibuprofen.

Now looking for some kind of link between Celebrex use and aortic valve disease, Bowler, Merryman and their team analyzed more than 8,600 relevant anonymous patient records from Vanderbilt University Medical Center. After correcting for certain risk factors, they found patients who took Celebrex saw a 20 percent increased incidence of valve disease.

“The main finding of this work was unexpected,” the authors wrote. “Primarily, celecoxib, the FDA-approved drug we anticipated being a potential therapeutic for CAVD, causes calcification in vitro and is associated with AS in patients. Conversely, the inactive analog dimethyl celecoxib showed the expected benefit of CDH11 blockade.”

Bowler et al. said further studies of dimethyl celecoxib are warranted, but that wasn’t the focus of their study. They said their overarching results suggest celecoxib—and therefore Celebrex—contributes to the development of CAVD, challenging the findings of an already widely accepted clinical trial.

“Considering the indications for celecoxib, these results suggest that physicians must carefully balance the risks of COX1 inhibition in the gut with those of COX2-specific inhibition in the aortic valve when choosing a pain control regimen, and use celecoxib with caution in elderly patients with risk factors for AS,” Bowler and colleagues wrote.